Selective CB2 agonists with anti-pruritic activity: discovery of potent and orally available bicyclic 2-pyridones.
Bioorg Med Chem
; 21(11): 3154-63, 2013 Jun 01.
Article
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| MEDLINE
| ID: mdl-23623258
ABSTRACT
The CB2 receptor has emerged as a potential target for the treatment of pruritus as well as pain without CB1-mediated side effects. We previously identified 2-pyridone derivatives 1 and 2 as potent CB2 agonists; however, this series of compounds was found to have unacceptable pharmacokinetic profiles with no significant effect in vivo. To improve these profiles, we performed further structural optimization of 1 and 2, which led to the discovery of bicyclic 2-pyridone 18e with improved CB2 affinity and selectivity over CB1. In a mouse pruritus model, 18e inhibited compound 48/80 induced scratching behavior at a dose of 100 mg/kg. In addition, the docking model of 18e with an active-state CB2 homology model indicated the structural basis of its high affinity and selectivity over CB1.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Prurito
/
Piridonas
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Compuestos Bicíclicos con Puentes
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Receptor Cannabinoide CB2
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Antipruriginosos
Límite:
Animals
Idioma:
En
Año:
2013
Tipo del documento:
Article